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Comparative analyses of the in vivo induction and transmission of ?-synuclein pathology in transgenic mice by MSA brain lysate and recombinant ?-synuclein fibrils.

ABSTRACT: ?-synuclein (?S) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized ?S fibrils or in vivo derived lysates containing ?S aggregates to induce the progressive spread of ?S inclusion pathology in animal disease models have supported the notion that ?S mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed ?S fibrils in hemizygous M20^+/- transgenic mice expressing wild type human ?S and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS ?S pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by ?S inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing ?S pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce ?S pathology following neonatal brain inoculation in transgenic mice expressing A53T human ?S (M83 line), but not in transgenic expressing wild type human ?S (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human ?S fibrils in hemizygous M83^+/- transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA ?S seeds that can induce pathology.

SUBMITTER: Dhillon JS

PROVIDER: S-EPMC6526622 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils.

Dhillon Jess-Karan S JS Trejo-Lopez Jorge A JA Riffe Cara C Levites Yona Y Sacino Amanda N AN Borchelt David R DR Yachnis Anthony Y AY Giasson Benoit I BI

Acta neuropathologica communications 20190520 1

α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We ha ...[more]

PMID: 31109378

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Project description:Parkinson's disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of α-synuclein fibrils to induce neurological disease in TgM83+/- mice expressing the A53T mutant of human α-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of α-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384 ± 131 days, respectively. Intravenous challenge with 50 µg of α-synuclein fibrils led to disease in 208 ± 20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of α-synuclein fibrils, which caused disease in 10 out of 10 mice in 202 ± 35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of α-synuclein fibrils developed disease in 156 ± 20 days and 133 ± 4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated α-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that α-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.

Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Dataset Information

Comparative analyses of the in vivo induction and transmission of ?-synuclein pathology in transgenic mice by MSA brain lysate and recombinant ?-synuclein fibrils.

Publications

Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils.

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